Alzheimer's disease (AD) is a degenerative disorder of the brain. It is the leading cause of dementia in elderly persons. AD patients have increased problems with memory loss and intellectual functions which progress to the point where they cannot function as normal individuals. With the loss of intellectual skills the patients exhibit personality changes, socially inappropriate actions and schizophrenia. AD is devastating for both victims and their families, for currently there is no effective palliative or preventive treatment for the inevitable neurodegeneration.
At a macroscopic level, the brains of AD patients are usually smaller, sometimes weighing less than 1,000 grams. At a microscopic level, the histopathological hallmarks of AD include neurofibrillary tangles (NFT), neuritic plaques, and degeneration of neurons. AD patients exhibit degeneration of nerve cells in the frontal and temporal cortex of the cerebral cortex, pyramidal neurons of the hippocampus, neurons in the medial, medial central, and cortical nuclei of the amygdala, noradrenergic neurons in the locus coeruleus, and the neurons in the basal forebrain cholinergic system. Loss of neurons in the cholinergic system leads to a consistent deficit in cholinergic presynaptic markers in AD.
The microtubule-associated protein known as Tau has been implicated in Alzheimers disease etiology. Tau binds to microtubules and assists with their formation and stabilization. However when tau is hyperphosphorylated, it is unable to bind and the microtubules become unstable and begin disintegrating. The unbound tau clumps together in formations called neurofibrillary tangles. More explicitly, intracellular lesions known as pretangles develop when tau is phosphorylated excessively and on improper amino acid residues. These lesions, over time, develop into filamentous neurofibrilary tangles (NFTs) which interfere with numerous intracellular functions.
Three different maturation states of NFT have been defined using anti-tau and anti-ubiquitin immunostaining. At stage 0 there are morphologically normal pyramidal cells showing diffuse or fine granular cytoplasmic staining with anti-tau. At stage 1 some delicate elongate inclusions are stained by tau antibodies; stage 2 is represented by the classic NFT demonstration with anti-tau staining; stage 3 is exemplified by ghost tangles where the host neuron has died, which are characterized by a reduced anti-tau but marked anti-ubiquitin immunostaining. It has been shown that the degree of cognitive impairment in diseases such as AD significantly correlates with the presence of neurofibrillary tangles.
The development of agents that can decrease cognitive decline, which may be a tauopathy, is of great interest for clinical and research purposes.